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External Beam Irradiation of Subfoveal Choroidal Neovascularization Complicating Age-Related Macular Degeneration
One-Year Results of a Prospective, Double-Masked, Randomized Clinical Trial
Dennis M. Marcus, MD;
W. Chris Sheils, MD;
Maribeth H. Johnson, MS;
Sandra B. McIntosh, PhD;
Diane B. Leibach, BA;
Albert Maguire, MD;
Judith Alexander, BA;
Chander N. Samy, MD
Arch Ophthalmol. 2001;119:171-180.
ABSTRACT
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Objectives To determine the effects of low-dose external beam irradiation compared
with observation on the visual function of eyes with subfoveal choroidal neovascularization
(CNV) complicating age-related macular degeneration (ARMD).
Design Prospective, double-masked, randomized clinical trial. Patients randomized
to the radiation group received external beam irradiation at a dose of 14
Gy in 7 fractions of 2 Gy. Patients randomized to the observation group received
sham radiation.
Setting Tertiary care retinal referral practice.
Patients Individuals with classic, mixed, or occult subfoveal CNV secondary to
ARMD.
Main Outcome Measures Change in visual acuity from baseline to specified time periods. Secondary
outcome variables were contrast sensitivity and fundus photographic/fluorescein
angiographic progression.
Results Forty-two eyes were randomized to observation; 41 eyes, to radiation.
Baseline characteristics and demographics did not differ between groups. The
median distance visual acuity (DVA) in radiation-treated eyes decreased from
20/80 at baseline to 20/320 (mean loss rate, 4.14 lines) at 1-year follow-up.
The median DVA in observation group eyes decreased from 20/125 at baseline
to 20/250 (mean loss rate, 3.39 lines) at 1-year follow-up. There were no
statistically significant differences in changes in DVA, contrast sensitivity,
or fluorescein angiographic progression from baseline between groups at any
follow-up period.
Conclusions At 1-year follow-up, low-dose external beam irradiation at 14 Gy in
7 fractions of 2 Gy is neither beneficial nor harmful for subfoveal CNV complicating
ARMD.
INTRODUCTION
LASER photocoagulation is a proven therapy for choroidal neovascularization
(CNV) complicating age-related macular degeneration (ARMD).1-7
The Macular Photocoagulation Study (MPS) has reported findings from randomized
trials of laser treatment for subfoveal neovascular lesions secondary to ARMD.4-6 Despite the long-term
benefit of laser treatment of subfoveal lesions within the context of the
MPS, the management of subfoveal CNV in ARMD remains controversial, as laser
treatment results in immediate visual loss after foveal ablation.8 In addition, the treatment of CNV in ARMD is based
on the accurate identification of CNV using fluorescein angiography. Most
patients with exudative ARMD demonstrate occult subfoveal CNV, which does
not have clinical and fluorescein angiographic features that meet the eligibility
criteria of the MPS for laser photocoagulation.9-10
Alternative, less destructive therapies that do not require angiographic identification
of the exact boundaries of subfoveal CNV are therefore essential.
Recently, photodynamic therapy with verteporfin has been demonstrated
to safely reduce the risk for visual loss in ARMD patients with predominantly
classic, subfoveal CNV.11 However, most verteporfin-treated
patients demonstrated visual acuity (VA) loss at 1 year follow-up.11 In addition, a recent pharmaceutical company press
release noted that photodynamic therapy with verteporfin had no significant
harmful or beneficial effect in ARMD patients with occult subfoveal CNV.12 Although the results of photodynamic therapy with
verteporfin are significant and encouraging, additional therapies are necessary
to find a benefit for occult CNV and to improve on the photodynamic therapy
outcomes for predominantly classic CNV.
Radiotherapy has been proposed as one such experimental treatment for
subfoveal CNV complicating ARMD. Experimental in vitro13-19
and in vivo20-26
studies demonstrate that the retinal endothelium and choriocapillaris are
radiosensitive. Clinical experience demonstrates that radiation is antiangiogenic
and is toxic to vascular tumors and endothelial cells.27-39
These properties of radiation have led to numerous nonrandomized studies evaluating
its effect on exudative ARMD. Most preliminary studies suffer from an absence
of adequate control groups or randomization, from short follow-up, and from
a lack of strict clinical and fluorescein angiographic entry criteria and
measurement.40-51
Although sound scientific rationale exists for offering radiotherapy in a
disease for which there is often inadequate or no treatment, there is no definitive
proof of a beneficial or harmful radiotherapy effect. We therefore performed
a prospective, double-masked, randomized, clinical trial to evaluate whether
low-dose external beam irradiation can decrease the risk for VA loss in ARMD
patients with subfoveal CNV.
PATIENTS AND METHODS
PATIENT SELECTION, ENTRY, AND FOLLOW-UP
Patients were recruited from one clinical center at the Department of
Ophthalmology, Medical College of Georgia, Augusta. Patients were enrolled
from February 3, 1995, through September 2, 1998. Patients with active subfoveal
CNV secondary to ARMD were eligible for inclusion in the study. Patients included
were older than 48 years and had not undergone previous laser therapy in the
study eye. Patients were excluded if there was a history of ocular disease
associated with CNV due to causes other than ARMD. To avoid a decreased threshold
for radiation complications, patients with diabetes or other forms of retinal
vascular disease and patients who received or were likely candidates for chemotherapeutic
agents were excluded. Patients who previously received ocular, orbital, or
periorbital radiation were excluded. Only one eye for any given patient was
eligible. Baseline VA of the study eye was required to be no worse than 20/400.
All patients were required to have clinical and fluorescein angiographic evidence
of active classic, occult, or mixed CNV for which the CNV itself, or contiguous
blood, was under the center of the foveal avascular zone. Patients with CNV
eligible for subfoveal laser therapy according to MPS guidelines4-6
were offered laser therapy, randomization to laser vs radiation therapy (data
not reported because of low patient recruitment), or observation vs radiation
therapy (present study). Patients with subfoveal CNV ineligible for laser
therapy according to MPS guidelines4-6
were offered randomization to observation vs radiation therapy (present study).
Patients with classic or predominantly classic CNV were eligible for this
study because photodynamic therapy with verteporfin was not proven or available
at that time.
All patients underwent a general ophthalmologic and retinal examination,
including tonometry, indirect ophthalmoscopy, and slitlamp biomicroscopy with
a contact 90- or 78-diopter lens. The following was measured at each study
baseline and follow-up visit: Best-corrected distance VA (DVA) was measured
at 10 feet on a backlit Early Treatment Diabetic Retinopathy Study chart.
The smallest line read with no less than 2 mistakes was recorded as the VA.
If VA was poor, the chart was brought closer to the patient in 1-foot increments
until the patient could read the largest line. Examination was performed to
determine the presence of radiation-induced adverse effects such as eyelid
erythema or dermatitis, madarosis, superficial punctate keratitis or dry eye,
cataract progression, retinal vasculopathy, iris or retinal neovascularization,
or optic disc edema or atrophy. Phakic eyes underwent assessment in the study
and nonstudy eyes for extent of nuclear sclerosis, cortical cataract, and
posterior cataract using a subjective 0 to 4 grading system. Phakic eyes underwent
Scheimpflug slit imaging of the lens52-53
in both eyes at preentry and at 6-month intervals to assess objectively for
cataract development or progression (data to be analyzed at 4-year follow-up).
Contrast threshold for large letters was measured at a distance of 1 m using
the Pelli-Robson chart.54 The contrast threshold
was scored as the level of contrast required to read at least 2 of the 3 letters
per contrast level presented on the eye chart. Color stereoscopic photography
and fluorescein angiography using a 30° camera (FF4 Fundus Camera; Zeiss/Humphrey,
Oberkochen, Germany) were performed.
A medical history was ascertained and data for possible contributing
factors to the outcome variables were collected, including age, sex, hypertension
or receiving an antihypertensive (yes or no), smoking status (no, quit, or
currently), aspirin or warfarin sodium (Coumadin) intake (yes or no), and
vitamin intake (yes or no). Baseline characteristics of CNV (classic, occult,
or mixed), baseline eligibility for laser according to MPS guidelines (yes
or no), and baseline size of CNV (MPS disc area) were graded by the Scheie
Eye Institute Photograph Reading Center, Philadelphia, Pa, and were analyzed
as possible contributing factors to the outcome variables.
Follow-up evaluations were performed at 3, 6, 12, and 24 weeks after
enrollment and at 6-month intervals thereafter for a total of 4 years. The
present study reports findings up to the 1-year follow-up. The patient, examining
ophthalmologist, and ophthalmic technician were unaware of the assignment
to observation or radiation treatment groups.
Eligible patients underwent an extensive explanation of randomization
and the experimental nature and possible complications of radiation treatment.
Medical College of Georgia institutional review board approval for both the
study and informed consent was obtained. Patients who were believed to satisfy
all eligibility criteria, including signed, written informed consent, were
assigned randomly at enrollment to receive radiation or to observation (sham
radiation). The randomization incorporated blocking, which is recommended
any time patient recruitment extends for a long period of time. Blocks of
size 2 or 4 were assigned randomly, and a separate random permutation was
used to assign the 2 treatments to the blocks. A randomization schedule was
printed and sent to the radiology team, who then sequentially allocated the
patients to the sham or actual radiation treatments. Radiation or sham treatments
were performed as soon as possible after enrollment, but no later than 2 weeks
after baseline examination and fluorescein angiography.
RADIATION PLANNING AND TREATMENT
Patients randomized to the radiation group underwent conventional simulation
followed by computed tomographic (CT) localization or by means of a CT simulator
in preparation for use of a small treatment port. Patients underwent simulation
in the supine position using a headrest and base plate (WFR/Aquaplast Corporation,
Wyckoff, NJ). After position check, reference marks were applied to the mask,
and an x-ray film was obtained with the simulator centered over the marker
of the treatment eye at a 15° angle anterior-posterior to the coronal
plane. Final reference marks were applied to the mask, followed by CT localization
in the simulation position using the mask and markers. Final beam position
was planned from CT images to ensure adequate coverage of the macula. The
radiation group was treated with a 6-MV photon beam using a machine field
setting of 3 cm wide by 4 cm long and a custom-fabricated treatment collimating
device with a semicircular shape of 1.5 cm wide by 3.0 cm long (1.5-cm radius;
3.0-cm diameter). Seven fractions of 2 Gy each (total, 14 Gy) were administered
during 7 consecutive business days in the radiation group. A dose of up to
14 Gy at 2 Gy per fraction was prescribed to the 90% isodose line.
SHAM RADIATION
The observation (sham) group did not undergo CT simulation. Patients
randomized to the observation group underwent 1 sham session with the radiation
oncologist (W.C.S.), who was not masked to group assignment. Sham sessions
were administered with the mask. Both groups adhered to identical follow-up
schedules to maintain the double-masked design. During review of the Medical
College of Georgia institutional review board–approved informed consent,
patients were informed that they would remain masked as to the group they
were randomized to and that they may receive sham or fake radiation. Patients
were informed that they would receive at most 7 treatments, but that they
may receive fewer sessions. Patients were informed that they or their insurance
carrier would not be charged for any of the costs associated with radiotherapy
or treatment planning.
DOSIMETRY
A special linear accelerator collimator was designed for this study
to minimize the dose to the lens and other out-of-beam structures. It consists
of a mounting assembly that attaches to the lowest part of the accelerator
head and a lead alloy plug that fits snugly into the tube extending from the
center of the mount (Figure 1 and Figure 2). The extended collimator assembly,
similar to that used for stereotactic radiosurgery, is external to the accelerator
head and provides additional protection because of the 10-cm added shielding
thickness. Because it is closer to the patient, the beam edge defined by the
external collimator has less penumbra and therefore a sharper dose falloff
at the beam edge.
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Figure 1. The patient is positioned in a
face mask (Aquaplast; WFR/Aquaplast, Wyckoff, NJ) for reproducibility of setup.
A special external collimating device is added to the head of the linear accelerator
to provide greater shielding than the adjustable tungsten collimators of the
accelerator alone. The beam, defined by a hole in the plug of the device,
is angled 15° to 20° toward the patient's posterior to avoid the contralateral
retina.
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Figure 2. The external collimator assembly
contains a lead alloy plug that is machined in its center to limit the beam
to a semicircular shape with a radius of 1.5 cm. A similar plug is displayed
outside the holding tube to demonstrate the thickness of the additional shielding
(approximately 10 cm).
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Two methods of dose measurement were used to determine doses to the
macula, lens, optic nerve, and retina of both eyes for a typical setup. A
small-volume ionization chamber was positioned in a block of polystyrene,
which is equivalent to tissue in regard to radiation dose distribution. A
typical mock-up of a patient treatment was used to determine doses at the
position of each relevant structure. The same measurement was performed using
thermoluminescent dosimeters in a polystyrene phantom. Finally, measurements
of lens dose made using the study setup were compared with doses measured
for a similar beam size (1.5 x 3.0 cm) using the linear accelerator
without external collimators.
MEASUREMENT VARIABLES AND STATISTICAL METHODS
The primary outcome variable measured at each examination was DVA. Secondary
outcome variables were contrast sensitivity (CS) and angiographic/photographic
appearance. Distance visual acuity was coded as integers so that the difference
between each line had a value of 1, and a difference of 3 integers (3 lines)
corresponded to a doubling of the visual angle. Distance visual acuity at
each time point was analyzed for group differences using the Wilcoxon rank
sum test. Kaplan-Meier curves were used to test the difference between the
treatment groups for the rate of decrease in DVA across the entire study time
frame. Changes in DVA from baseline were analyzed using t tests if there were 2 groups undergoing testing, or analysis of variance
(ANOVA) if there were more than 2 groups or when testing possible contributing
factors.
Contrast sensitivity values recorded from the Pelli-Robson chart are
the base-10 logarithm of CS, which has the advantage that equal steps on this
scale correspond to equal effects. Treatment differences in logarithm of CS
were analyzed using t tests. Percentage of contrast
is reported, which is the reciprocal of CS.
Fluorescein angiograms and color photographs were reviewed and graded
in a masked manner with respect to randomization group. Baseline fluorescein
characteristics, as outlined above, were graded for type, laser eligibility,
and size by the reading center in a masked fashion. Grading of follow-up angiograms
and all color photographs were performed by one of us (D.M.M.) in a masked
fashion. Fluorescein angiograms and color fundus photographs were graded as
to CNV size ( 1, >1 to 2, >2 to 3.5, >3.5 to 4, >4 to 6,
>6 to 9, and >9 MPS disc areas); CNV size plus blood, elevated blocked
fluorescence, or serous pigment epithelial detachments (CNV size + all) (1,
>1 to 2, >2 to 3.5, >3.5 to 4, >4 to 6, >6 to 9, and >9
MPS disc areas); classic CNV size (none, 1, >1 to 2, >2 to 3.5,
>3.5 to 4, >4 to 6, >6 to 9, and >9 MPS disc areas); hemorrhage
(none, 25% of clinical macula, and >25% of clinical macula, arcade to
arcade); and subretinal fibrosis (none, 25% of clinical macula, and >25%
of clinical macula, arcade to arcade). For grading of follow-up angiograms
and photographs, when there was an increase in size of the membrane and/or
increase in hemorrhage or subretinal fluid from baseline, the membrane was
graded as worsened. When there was no change in the size of the membrane without
increased hemorrhage or subretinal fluid, the membrane was graded as stable.
In occult lesions obscured by blood, if the extent of the membrane was visualized
further after clearing of blood, the membrane was graded as stable. When there
was a decrease in the degree of leakage or membrane size with improvement
in hemorrhage or subretinal fluid, the membrane was graded as improved.
We used  2 testing when analyzing categorical data unless
the cells sizes were too small; if so, Fisher exact tests were used.55
Randomized, clinical trials investigating treatments of CNV with a classic
component indicate that approximately 27%11
to 30%4 of observed eyes exhibit 6 lines or
more of visual loss at 1 year. If a 30% 6-line loss rate was reduced to 10%
in the radiation treatment group, then a sample size of 50 in each group would
be needed to have 80% power to detect this 20% difference when  = .05.
Randomized, clinical trials investigating treatments for occult CNV without
a classic component indicate that approximately 55% of observed eyes exhibit
3 lines or more of visual loss at 1 year.12
If a 55% 3-line loss rate was reduced to 30% in the radiation group, then
a sample size of 50 in each group would be needed to have 80% power to detect
this 20% difference when = .05. Data were reviewed semiannually by
two of us (D.M.M. and M.H.J.) for evidence of treatment benefit or harm. In
November 1998, a decision was made to stop enrollment into the trial and continue
follow-up, since the group differences at 1 year were very small and were
not approaching 20%.
RESULTS
DOSIMETRY
Results of ionization chamber and thermoluminescent dosimeter measurement
agreed within 4% of the prescribed dose for all points of measurement within
the mock patient setup. Table 1
summarizes the actual doses received at each point by ionization chamber and
thermoluminescent dosimeters along with the toxic dose for the structure.
The beam path is shown as a 2-dimensional isodose distribution in Figure 3. Exact points of measurement are
annotated on the CT scan of Figure 4
along with ion chamber doses expressed as a percentage of the prescribed dose
to the ipsilateral macula.
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Table 1. Doses to Sensitive Structures*
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Figure 3. A 2-dimensional computed tomographic
slice from a typical patient is used to display a computer-calculated isodose
distribution. The small white area represents the volume receiving the prescribed
dose of 14 Gy. The red area is 90% of the prescribed dose; yellow, 70%; aqua,
50%; and pink, 30%. Doses to out-of-beam structures are too low to be displayed
on the computer plan.
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Figure 4. Points selected for ionization
chamber and thermoluminescent dosimeter measurement are marked, and the measured
percentage of the prescribed dose at each point (ion chamber) is displayed.
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Dose measurements using the external collimator constructed for the
study were compared with the dose without added external collimation (1.5
x 3.0 cm). The doses to ipsilateral and contralateral lens were reduced
to 50% of the original dose using the collimator.
BASELINE CHARACTERISTICS AND FOLLOW-UP
A total of 83 eyes were assigned randomly to radiation treatment or
to observation (sham radiation). Forty-one eyes were randomized to the radiation
group, and 42 were assigned to the observation group. The number of eyes followed
up for specific periods is outlined in Table 2. Of all 83 randomized eyes, 70 (84%) were examined at 1
year after enrollment.
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Table 2. Data Distribution at 1-Year Follow-up*
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The distributions of baseline factors are outlined in Table 3 and were examined for differences between the radiation
and observation groups. Variables were similarly distributed between groups.
However, patients randomized to the radiation group were more likely to have
hypertension and/or treatment with antihypertensive medication.
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Table 3. Demographic and Baseline Data*
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VISUAL FUNCTION OUTCOMES
The VA distributions for patients examined 3 weeks, 6 weeks, 12 weeks,
6 months, and 12 months after randomization are outlined in Table 4. Although we measured DVA at 10 feet, we report the results
using the more readily recognized and meaningful VA score with a numerator
as 20 feet (ie, a measurement of 10/40 is reported as 20/80). The median DVA
in radiation-treated eyes decreased from 20/80 at baseline to 20/320 at 1-year
follow-up. The median DVA in observation group eyes decreased from 20/125
at baseline to 20/250 at 1-year follow-up. There were no statistically significant
differences for median VA between groups at any follow-up period.
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Table 4. Visual Acuity Distribution by Time and Treatment*
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The distribution of change in DVA from the initial visit is outlined
in Table 5 for patients examined
3 weeks, 6 weeks, 12 weeks, 6 months, and 12 months after randomization. There
were no statistically significant differences in changes in DVA from baseline
between groups at any follow-up period. At 1-year follow-up, eyes in the radiation
and observation groups lost a mean of 4.14 and 3.39 lines, respectively, of
DVA. Possible contributing factors at baseline such as age, sex, VA, status
of contralateral nonstudy eye (exudative or nonexudative), smoking status,
anticoagulant intake, hypertension history, and vitamin intake were analyzed
for effect on VA outcomes and were found not to affect VA changes at 1 year
(data not shown).
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Table 5. Visual Acuity Change From Baseline by Time and Treatment*
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The percentage of eyes in the radiation and observation groups with
a decrease in VA of 3 lines or more (moderate visual loss) and 6 lines or
more (severe visual loss) is illustrated in Figure 5. There were no statistically significant differences in
the development of moderate or severe visual loss between groups at any follow-up
period.
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Figure 5. Kaplan-Meier curves demonstrating
proportion of eyes with 3 or more (A) and 6 or more (B) lines of visual acuity
loss over time for the observation and radiation groups.
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The contrast threshold was compared between groups (Table 6). There were no statistically significant differences in
the development of severe contrast loss between groups at any follow-up period.
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Table 6. Contrast Sensitivity Threshold by Time and Treatment*
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FLUORESCEIN ANGIOGRAPHY AND FUNDUS PHOTOGRAPHY
Fluorescein angiography was performed at all visits for 26 (62%) of
42 patients in the observation group and for 33 (80%) of 41 patients in the
radiation group. Mild allergic symptoms developed in 1 patient in the observation
group who did not receive follow-up angiography. Observation and radiation
groups did not differ at baseline with regard to various fluorescein angiographic
features (Table 3). For both groups,
VA line loss rates at 1-year follow-up were not statistically different for
eyes with classic, mixed, or occult CNV or with laser-eligible CNV at baseline
(data not shown).
Sizes of CNV, of CNV + all, and of classic CNV at baseline did not influence
VA loss rates (data not shown). Growth rates of CNV did not differ between
the randomization groups. The observation and radiation groups demonstrated
a mean increase in CNV size at 1-year follow-up of 1.21 and 1.83 categories,
respectively (P = .13). The observation and radiation
groups demonstrated a mean increase in size of CNV + all at 1-year follow-up
of 1.24 and 1.86 categories, respectively (P = .15).
The observation and radiation groups demonstrated a mean increase in classic
CNV size at 1-year follow-up of 1.75 and 2.06 categories, respectively (P = .69).
At baseline, 20 of 42 observation group eyes and 23 of 41 radiation
group eyes demonstrated some blood on fundus photography (Fisher exact test, P = .51). For both groups, the presence or absence of blood
at baseline did not influence VA loss rates (data not shown). There was an
exception in that, for eyes with blood at baseline, 6-line loss rates were
higher for eyes in the radiation group (ANOVA, P
= .04). The extent or development of bleeding did not differ between groups
in eyes where blood was absent at baseline (data not shown).
At baseline, 4 of 42 observation group eyes and 2 of 41 radiation group
eyes demonstrated some fibrosis on fundus photographic findings (Fisher exact
test, P = .68). For both groups, the presence or
absence of fibrosis at baseline did not influence VA loss rates (data not
shown). The extent or development of fibrosis did not differ between groups
in eyes where fibrosis was absent at baseline (data not shown).
At 1-year follow-up, 21 of 33 observation group eyes and 30 of 37 radiation
group eyes were graded as worsened using fluorescein angiographic and/or fundus
photographic findings; no statistically significant differences in fluorescein
angiographic and/or fundus photographic deterioration were found (P = .10) (Figure 6).
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Figure 6. Bar graph demonstrating percentage
of eyes with angiographic and/or photographic worsening at different time
points for each group.
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COMPLICATIONS
No evidence of acute or subacute toxic effects of radiation was observed.
None of the patients in the observation and radiation groups experienced phosphenes
during the sham or radiotherapy sessions. Radiation-related optic neuropathy
or retinopathy was not observed in either group. Two patients received a diagnosis
of diabetes mellitus after enrollment. Radiation-related retinopathy and diabetic
retinopathy did not develop in any patient.
Cataract progression was defined as the clinical
grade (0-4) increasing by 1 or more grade at 1 year after baseline for nuclear
sclerosis, cortical changes, and posterior subcapsular cataract (PSC). There
were 28 and 12 phakic eyes in the radiation and observation groups, respectively.
At 1-year follow-up, 8 of 28 phakic eyes and 3 of 12 phakic eyes demonstrated
nuclear sclerosis cataract progression in the radiation and observation groups,
respectively. At 1-year follow-up, 7 of 28 phakic eyes and 3 of 12 phakic
eyes demonstrated cortical cataract progression in the radiation and observation
groups, respectively. All 12 phakic eyes in the observation group demonstrated
no evidence of PSC at baseline, and PSC had not developed in any of these
eyes at 1-year follow-up. In the radiation group, 23 phakic eyes demonstrated
no evidence of PSC at baseline; some PSC developed in 1 of the 23 eyes at
1-year follow-up. In the radiation group, 5 phakic eyes demonstrated PSC at
baseline; none of these 5 eyes demonstrated PSC progression at 1-year follow-up.
At 1-year follow-up, there were no differences in the rate of cataract progression
between radiation and observation groups for nuclear sclerosis, cortical changes,
and PSC (Fisher exact 2-tail test, P.99 for all
3 conditions).
One patient in each group with MPS laser-eligible CNV that had progressed
after enrollment elected subfoveal laser photocoagulation ablation. Rhegmatogenous
retinal detachment with vitreous hemorrhage developed in 1 patient in the
radiation group during the study period; a large, nonclearing vitreous hemorrhage
developed in another radiation group patient.
COMMENT
The results of our randomized study suggest that low-dose external beam
irradiation at a dose of 14 Gy in 7 fractions of 2 Gy is not beneficial for
subfoveal CNV complicating ARMD. No difference in VA, CS, or fluorescein angiographic
progression was found between the observation and radiation groups at any
follow-up period. Most patients in the radiation group demonstrated evidence
of angiographic and/or fundus photographic progression of CNV without a diminished
extent of fibrosis or subretinal hemorrhage, compared with patients in the
observation group. No significant complications, such as radiation retinopathy,
optic neuropathy, or cataract, were identified in radiation-treated patients.
Although longer follow-up is necessary to determine if such complications
develop, radiotherapy at this dose does not appear to be harmful at 2-year
follow-up.
Radiation therapy, a treatment with known antiangiogenic properties,
has been investigated as a modality to prevent severe visual loss in exudative
ARMD. Since the report by Chakravarthy and coworkers40
in 1993, many patients worldwide have received varying forms of radiation
for this disease. Nonrandomized, uncontrolled studies40-51
indicate that radiation therapy for CNV does not have significant short-term
adverse effects, does not cause immediate visual loss, and does not require
complete angiographic visualization. Conclusions of most reports studying
radiotherapy are limited by short follow-up, small numbers of cases, retrospective
data collection, absence of standardized VA measurement, absence of strict
angiographic and visual entry criteria, and absence of an appropriate randomized
control group.40-51
Most of these uncontrolled, nonrandomized studies have used external beam
irradiation with standard fractions of approximately 2 Gy to a total dose
of 10 to 20 Gy. Some investigators have reported minimal or no therapeutic
external beam irradiation effect,48-50
whereas others have reported a moderate benefit with standard fractions.40-46
Higher fractions and doses of external beam irradiation41
and other modalities such as brachytherapy42, 51
or proton beam irradiation47 also have been
examined. Nonstandard fractions of external beam irradiation (6- to 8-Gy fractions)41 and proton beam irradiation (8- and 14-Gy fractions)47 have been proposed as beneficial therapy in uncontrolled,
nonrandomized studies. Some evidence of angiographic regression of CNV has
been observed with higher fractions, especially after proton beam irradiation.
Two randomized, published studies comparing radiation with observation
have used higher nonstandard fractions.56-57
Bergink and coworkers56 randomized 74 patients
with classic, mixed, or occult subfoveal CNV to observation vs external beam
irradiation. Four fractions of 6 Gy (total dose, 24 Gy), a significantly higher
total dose and fraction size than in our study, were used. At 1-year follow-up,
52% of the observation group vs 32% of the radiated group lost 3 or more lines
of VA (P = .03). Six or more lines of VA loss were
observed in 41% of the observation group vs 9% of the radiation group (P = .002). A greater beneficial treatment effect was observed
for mixed or occult CNV than for classic CNV. Although radiotherapy seemed
to have a stabilizing effect, a significant proportion of irradiated eyes
lost VA, and irradiated eyes demonstrated progressive growth of CNV.56 Char and coworkers57
performed a small randomized trial of 27 eyes with classic and occult subfoveal
CNV. Patients were randomized to observation vs external beam irradiation
(single fraction of 7.5 Gy). The mean VA line loss was 1.9 in radiation group
eyes vs 5.5 in observation group eyes (P = .05).
Similar to the study by Bergink and coworkers,56
Char and coworkers57 found no difference in
angiographic progression between eyes in radiation and observation groups.
The results of our study show that the likelihood of a beneficial effect
using a 14-Gy dose in 2-Gy fractions is very low. However, a significant proportion
of our study eyes demonstrated occult CNV as opposed to other radiotherapy
studies, which have required enrolled eyes to demonstrate a component of classic
CNV. Many of the analyses examining possible differences among demographic,
angiographic, and photographic subgroups deal with small numbers and had low
power to find differences. Limitations exist in that a larger sample size
might identify a small harmful or beneficial treatment effect for various
subgroups (ie, classic vs occult CNV). The lack of treatment benefit in our
randomized study may also be due to the use of sham radiation in the observation
group. We have demonstrated that our technique of sham radiation keeps patients
guessing as to which group they were randomized.58
The absence of patient masking may create bias in studies examining subjective
psychovisual outcome variables such as VA. Uncontrolled radiotherapy studies
that found a small beneficial effect at similar dose and fraction sizes also
may have been influenced by such a phenomenon in patients who know they are
receiving a "treatment." The Radiation Therapy for Age-related Macular Degeneration
Study Group59 demonstrated an absence of treatment
benefit in a randomized, multicenter radiotherapy trial using 8 fractions
of 2 Gy (total, 16 Gy). Their study, similar to ours, used sham radiation
and had a large proportion of eyes demonstrating occult CNV.
The absence of any efficacy in our randomized trial, despite the initially
promising retrospective studies, highlights the need for caution in evaluating
radiotherapy or other experimental treatments for exudative ARMD. However,
in light of the beneficial visual outcomes demonstrated in randomized radiotherapy
trials using higher fractions and doses, the favorable angiographic response
observed with higher doses and fraction sizes, and the sound scientific and
clinical rationale for radiotherapy, we believe that radiotherapy should not
be eliminated as a potential therapy. Although ours and other studies using
a safe and low dose with standard fractions of external beam irradiation did
not show VA improvement or fluorescein angiographic regression, use of nonstandard
fractions, higher total doses, and extramacular sparing techniques (ie, brachytherapy,
charged particle irradiation, and gamma ray knife) may be beneficial. It is
hoped that ongoing and future randomized trials will provide useful information
for determining whether a therapeutic window for radiotherapy exists.
AUTHOR INFORMATION
Accepted for publication July 31, 2000.
Supported in part by an Unrestricted Departmental Award from Research
to Prevent Blindness, New York, NY, and by grants from the Knights Templar
Educational Foundation of Georgia, Macon.
Corresponding author and reprints: Dennis M. Marcus, MD, Medical
College of Georgia, Department of Ophthalmology, 1120 15th St, Augusta, GA
30912 (e-mail: dmarcus{at}mail.mcg.edu).
From the Department of Ophthalmology (Dr Marcus and Ms Leibach), the
Section of Radiation Oncology, Department of Radiology (Drs Sheils and McIntosh),
and the Office of Biostatistics (Ms Johnson), Medical College of Georgia,
Augusta; the Department of Ophthalmology, University of Pennsylvania Health
Systems, Philadelphia (Dr Maguire and Ms Alexander); and Ocala Eye Surgeons,
Ocala, Fla (Dr Samy).
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